Outcomes after stereotactic radiosurgery of brain metastases in patients with malignant melanoma and validation of the melanoma molGPA.

INTRODUCTION: Malignant melanoma is the third most common primary in the diagnosis of brain metastases. Stereotactic radiosurgery (SRS) is a well-established treatment option in limited brain disease. We analyzed outcomes of SRS with a particular focus on the graded prognostic assessment (GPA, melanoma molGPA), prognostic factors, and toxicity. METHODS: We evaluated 173 brain metastases in 83 patients with malignant melanoma. All were treated with SRS median dose of 20 Gy prescribed to the 80 or 100% isodose line between 2002 and 2019. All patients were followed-up regularly, including contrast-enhanced brain imaging as well as clinical examination, initially 6 weeks after treatment, then in quarterly follow-up. RESULTS: The median age was 61 years (range 27-80); 36 female and 47 male patients were treated. After a median follow-up of 5.7 months, median OS (overall survival) was 9.7 months 95%-KI 4.7-14.7). LC (local control) at 6 months, 12, 24 months was 89%, 86%, and 72%, respectively (median was not reached). Median DBC (distant brain control) was 8.2 months (95%-KI 4.7-11.7). For OS, a KPS ≥ 80%, a positive BRAF mutation status, a small PTV (planning target volume), the absence of extracranial metastases, as well as a GPA and melanoma molGPA > 2 were prognostic factors. In the MVA, a small PTV and a melanoma molGPA > 2 remained significant. CONCLUSION: The present survival outcomes support the use of the disease-specific melanoma molGPA as reliable prognostic score. Favorable outcomes for SRS compared to other studies were observed. In the treatment of brain metastases of malignant melanoma patients, a multidisciplinary approach consisting of surgery, SRS, chemotherapy, and immunotherapy should be considered.

Maternal use of antiepileptic drugs and the risk of major congenital malformations: a joint European prospective study of human teratogenesis associated with maternal epilepsy.

PURPOSE: To quantify the risks of intrauterine antiepileptic drug (AED) exposure in monotherapy and polytherapy. METHODS: Data from five prospective European studies totaling 1,379 children were pooled and reanalyzed. Data were available for 1,221 children exposed to AED during pregnancy and for 158 children of unexposed control pregnancies. RESULTS: Overall, when comparing a subgroup of 192 children exposed to AED with 158 children of matched nonepileptic controls, there was an increased risk of major congenital malformations (MCA) in children exposed to AED during gestation [relative risk (RR) 2.3; 95% confidence interval (CI): 1.2-4.7]. A significant increase in risk was found for children exposed to valproate (VPA) (RR 4.9; 95% CI: 1.6-15.0) or carbamazepine (CBZ) (RR 4.9; 95% CI: 1.3-18.0) in monotherapy. When comparing different AED regimens during all 1,221 pregnancies, risks of MCA were significantly increased for the combination of phenobarbital (PB) and ethosuximide (RR 9.8; 95% CI: 1.4-67.3) and the combination of phenytoin, PB, CBZ, and VPA (RR 11.0; 95% CI: 2.1-57.6). Offspring of mothers using > 1,000 mg VPA/day were at a significantly increased risk of MCA, especially neural tube defects, compared to offspring exposed < or =600 mg VPA/day (RR 6.8; 95% CI: 1.4-32.7). No difference in risk of MCA was found between the offspring exposed to 601-1,000 mg/day and < or =600 mg/day. CONCLUSIONS: This reanalysis shows that VPA is consistently associated with an increased risk of MCA in babies born to mothers with epilepsy. Significant associations were also observed with CBZ. Larger prospective population-based studies are needed to evaluate the risks of many other less frequently prescribed treatment regimens, including newly marketed AEDs.

Insulin-like growth factor I correlations to changes of the hormonal status in puberty and age.

IGF-I is considered to be one of the most important growth factors during puberty. Information concerning its correlation to thyroid hormones (T3, T4), adrenal and sex steroids is limited to puberty and the elderly. The presented study included 455 subjects (among them 259 children) ranging in age from newborn to 100 years. Serum IGF-I concentrations increase from childhood to the end of puberty (2 years earlier in girls). There are close positive correlations between IGF-I concentrations and age, height and weight and between IGF-I and estradiol or testosterone concentration in girls and boys respectively, and the DHEA-S level in boys during puberty. Correlations also exist with T3, aldosterone and 17 OH-progesterone in boys and girls in the pubertal stages I-V and with T4 in stages I-IV. Compared to 20-30 year-old subjects IGF-I concentrations amounted to 59% after 60 years, 43% in men and 54% in women after 70 years and 29% after 90 years. It is suggested that increasing adrenal DHEA-S concentrations stimulate IGF-I synthesis and by means of gonadal steroidogenesis, increase the pubertal GH secretion and the further pubertal IGF-I increase. The low IGF-I concentrations in patients > 60 years reflect the more catabolic metabolism of the elderly.

Major and minor birth malformations and antiepileptic drugs.

In a study of infants of parents with epilepsy, malformations were twice as prevalent in these children as in controls. Children of mothers with epilepsy had more minor anomalies than those of fathers with epilepsy or controls. At 1 year of age, a greater number of minor anomalies was seen in children of mothers with epilepsy who had received treatment with antiepileptic drugs (AEDs) during pregnancy, whereas at 4 years, no difference was observed. Type of epilepsy, seizures during pregnancy, plasma levels of phenytoin or phenobarbital in the medium range, and fetal intrauterine growth did not correlate with the number of minor anomalies. We suggest that the special genetic background that predisposes to epilepsy also renders the fetus more vulnerable to major and minor anomalies. Although linkage between epilepsy and malformation is stronger than between AEDs and malformations, valproate, phenytoin, and phenobarbital show specific teratogenic effects. In addition, all AEDs unspecifically increase the number of minor anomalies. Under therapeutic conditions, valproate may be regarded as considerably teratogenic and all other observed AEDs as weakly teratogenic.

Fetal growth, major malformations, and minor anomalies in infants born to women receiving valproic acid.

The association of fetal and neonatal distress, birth measurements, major malformations, and minor anomalies was studied prospectively in 14 infants of women with epilepsy who were receiving valproic acid (VPA) monotherapy and in 12 infants of women with epilepsy who were receiving VPA in combination with other anticonvulsant drugs. Comparison was made with 26 matched-pair controls and 116 controls from a larger study of antiepileptic drugs. During the first trimester, total VPA serum concentrations were well above therapeutic levels (100 to 184 micrograms/ml) in two women receiving high VPA doses (2000 and 1500 mg daily). Although dosage remained the same, serum concentrations decreased during pregnancy to therapeutic levels (33.9 to 57.0 micrograms/ml). The VPA percent free fraction increased in the third trimester and was threefold higher at birth. Almost half of the infants exposed to VPA monotherapy were distressed during labor, and 28% had low Apgar scores. Fetal and neonatal distress may be caused by the high VPA percent free fraction during labor and at birth. Mean body measurements at birth after VPA monotherapy were comparable to those in the matched control group, but were reduced in the group of infants receiving VPA combination therapy. Four infants exposed to VPA monotherapy were born with major malformations. The median number of minor anomalies was four times higher in infants whose mothers received VPA alone or VPA combination therapy than in controls. Seven infants had a pattern of craniofacial and digital anomalies that was distinctly different from that observed after in utero exposure to other anticonvulsant medications. The occurrence of major malformations and the number of minor anomalies may be dose related.

Carbamazepine and carbamazepine-10,11- epoxide during pregnancy and postnatal period in epileptic mother and their nursed infants: pharmacokinetics and clinical effects.

A total of 11 epileptic mothers treated with carbamazepine (CBZ) as well as their 12 newborns were included in this study. Maternal CBZ concentrations remained rather constant during pregnancy and slightly increased after parturition. Carbamazepine-10, 11-epoxide ( CBZE ) levels were less predictable and either increased or decreased during pregnancy. Fetal/maternal serum concentration ratios at birth were 0.78 +/- 0.14 (n = 5) for CBZ and 0.75 +/- 0.09 (n = 5) for CBZE . Neonatal half-lives were 28 +/- 11 hours (n = 4) for CBZ and 20 and 24 hours (n = 2) for CBZE . maternal milk/serum concentration ratios of CBZ and CBZE were 0.39 +/- 0.22 (N = 11) and 0.49 +/- 0.28 (n = 6), respectively. The steady-state CBZ serum levels of nursed infants were about 1.0 micrograms/ml in all cases but one, where a maximum concentration of 4.7 micrograms/ml was reached. One of the infants had major malformations. Minor anomalies were less frequent in the CBZ group, compared to the whole group of infants exposed to anticonvulsive drugs other than CBZ and as frequent as in a matched pair control group of unexposed neonates. Neonatal somatic data were found to be below the corresponding values of neonates exposed to antiepileptic drugs other than CBZ.